DESCRIPTION: IRES elements are novel genetic elements identified in eukaryotic mRNA that regulate initiation of translation independently of a 5' end of a template. This research will continue studies on the structure and function of viral IRESes, particularly those of picornaviruses discovered in the P.I.s laboratory in 1987. As an extension of the previous aims, the P.I. will also study the IRES element of hepatitis C virus (HCV), an agent causing widespread disease world-wide. The P.I. will determine the parameters of tissue specific expression of IRES function, a project with specific reference to the neurovirulence character of picornaviruses. Moreover, he plans to dissect the structure/function relation of IRES elements of poliovirus, encephalomyocarditis virus (EMCV), and HCV with respect to cis-acting elements and trans-acting factors. The studies will be carried out by genetic manipulations of viral genomes, by a novel procedure called yeast three-hybrid system, and by molecular biological and biochemical procedures. The tool for studying the HCV IRES will be a novel poliovirus/HCV chimeric virus whose translation is solely controlled by the HCV IRES.